This A1 translational therapeutic research proposal seeks to enhance fracture repair with a locally delivered parathyroid hormone (hPTH1-34) as a fracture repair enhancing factor in the setting of impaired fracture healing as seen in diabetic patients, chronic smokers, and elderly people with the goal of avoiding fracture- associated complications. Existing literature (Clinical Premise) and our preliminary Data (Scientific Premise) suggest that osteochondral fracture-activated stem cells (FASCs) are low in number or functionally less robust in elderly patients, T2DM patients, and chronic smokers than in young healthy subjects. Although hormones classically act on target cells at the remote sites through secondary messengers or directly, PTH is a paradoxical hormone. From an endocrine perspective, PTH is well known to have bone catabolic or anabolic functions depending on high vs. low doses or continuous vs. intermittent systemic administration. Despite presumed beneficial effects of systemic intermittent PTH treatments on fracture healing, effects of locally delivered PTH on fracture healing are not well known. It is scientifically logical and clinically pragmatic to deliver PTH locally at the fracture site if PTH receptors are expressed by the FASCs. The goal of this research program is to establish a new pragmatic and cost-effective way of enhancing impaired fracture healing with a locally delivered PTH1-34 that directly boost FASCs with PTH-receptors at the fracture site during the early critical phase of FASC proliferation and differentiation. Our preliminary data showed identification of FASCs with PTH receptors; optimization of localized PTH release kinetics and optimal dose justification in vivo and in vitro; decreased number or function of FASCs and therapeutic rescue of impaired fracture healing by locally delivered PTH1-34 in elderly, T2DM, or chronic cigarette-smoking mice; and secondary anabolic BMP2/4 production by locally delivered PTH in vivo. We posit a central hypothesis that locally delivered PTH results in superior fracture healing by increasing the population of and enhancing differentiation of Fracture Activated Stem Cells (FASCs) in aged, Type 2 diabetic, or chronic smoker subject. In order to maximize clinical impact, we will test whether hPTH1-34 enhances proliferation and early osteo-/chondral/angiogenic-differentiation of FASCs in elderly subjects (Aim 1), in 3 different clinically relevant T2DM mouse models, and chronic cigarette smoking mice (Aim 3). Our dose-escalated experiments and analysis will be blinded in order to simulate rigorous clinical trials. Translational innovation and impact lie in establishment of a simple, pragmatic, and cost-effective therapeutic platform to use locally delivered PTH as a fracture-healing enhancer in impaired fracture healing in aged, T2DM, and chronic cigarette smoking subjects, which are 3 most commonly seen types of impaired fracture healing in clinical orthopaedic surgery.